Sapropterin hydrochloride (L-tetrahydrobiopterin dihydrochloride) is a drug used in treating hyperphenylalaninemia. Hyperphenylalaninemia is a disease caused by a defect in a gene which exhibits symptoms including central nervous symptoms such as mental retardation, melanin deficient symptoms, and abnormal urine odor, all of which are caused by abnormal phenylalanine metabolism.
Sapropterin hydrochloride is produced by using 1′,1′-diethylsulfonyl-L-rhamnose for the starting material to produce L-biopterin, and reducing this L-biopterin (see non-patent documents 1 and 2 and patent documents 1 to 5). In these documents, sapropterin hydrochloride is isolated as crystals, and these documents are utterly silent about stability of the crystals.
[Non-patent document 1] Helv. Chim. Acta, 68(6), 1639-1643 (1985)
[Non-patent document 2] Helv. Chim. Acta, 61, 2731 (1978)
[Patent document 1] Japanese Patent Publication No. 2-12475
[Patent document 2] Japanese Patent Publication No. 4-13357
[Patent document 3] Japanese Patent Publication No. 5-86393
[Patent document 4] Japanese Patent No. 2711828
[Patent document 5] Japanese Patent Application Laid-Open No. 9-157270
The crystals of sapropterin hydrochloride produced by the methods as described above were problematic in terms of thermal stability and hygroscopicity, and there has been a demand for development of a method which enables stable supply of highly stable crystals.